Risk factors and prognosis for the development of acute kidney injury in patients using colistin in the intensive care unit: A retrospective cohort study

Colistin, an antibiotic of polymyxin group, has recently been increasingly used in the treatment of multidrug resistant gram-negative bacteria. However, it has serious adverse effects such as acute kidney injury (AKI). We aimed to determine the factors affecting the development of AKI due to colistin, which has serious adverse effects, such as nephrotoxicity and neurotoxicity. We retrospectively analyzed the data of patients who received colistin for multidrug resistant gram-negative sepsis in adult intensive care units between January 2020 and December 2022. Demographic data, blood test results, concomitant drug use, need for renal replacement therapy, and mortality were recorded. Kidney damage was assessed according to the Kidney Disease Improving Global Outcomes criterion. We obtained data from 103 patients, 45 (43.7%) of whom were women. The most common comorbidity was a neurological disorder. Renal damage developed in 59.2% of patients. Renal replacement was required in 50.8% of the patients. Among patients who received colistin, 64.1% died. The use of vasopressors, diuretics, nephrotoxic agents with colistin, advanced age, and hypoalbuminemia were more common in patients with renal injury. Multivariate regression analysis showed that vasopressor use, prior creatinine elevation, and diuretic use were independent risk factors for colistin-induced AKI. Vasoactive agent use, previous kidney injury, and furosemide use were independent risk factors for colistin-induced nephrotoxicity. Considering these factors may be instructive for better monitoring of patients when colistin is required in intensive care units.


Introduction
Colistin, an antibiotic belonging to polymyxin group, is used in the treatment of multidrug-resistant (MDR) gram-negative microorganisms, mainly Acinetobacter baumannii. [1]Although its use decreased due to its nephrotoxic and neurotoxic effects, the demand has increased again in recent years due to increasing MDR. [2]Nephrotoxicity involves oxidative stress, inflammatory pathways, and apoptosis, and its incidence rate is up to 60% in patients using colistin. [3]Reaching a consensus regarding the factors affecting kidney injury in patients receiving colistin is challenging due to the lack of clarity about the diseases, the use of different parameters in defining the kidney damage, and the use of multiple treatments and devices in intensive care units (ICUs). [4,5]psis is one of the most common causes of acute kidney injury (AKI) in ICUs, resulting in high morbidity and mortality.Further, polypharmacy, the use of vasoactive agents, and other effects of sepsis may increase AKI development and mortality. [6,7]KI is clinically defined according to the serum creatinine level and urine output.The Kidney Disease Improving Global Outcomes (KDIGO), an international consensus criterion, is the most commonly used definition.Risk, injury, failure, and end-stage (RIFLE) and Acute Kidney Injury Network (AKIN) criteria were used in defining AKI.Markers such as neutrophil gelatinase-associated lipocalin, IL-18, kidney injury molecule-1, and liver-type fatty acid-binding protein are indicators of tubular damage. [8]is research received no specific grants from any funding agency in the public, commercial, or not-for-profit sectors Patients' consent was not obtained due to the retrospective design of the research.
This study aimed to define the development of AKI and factors affecting it based on the KDIGO criterion in patients receiving colistin in the ICUs.

Methods
We retrospectively analyzed the data of patients who received colistin for MDR gram-negative sepsis in adult ICUs of Bolu Izzet Baysal State Hospital between January 2020 and December 2022.Sex, comorbidities, age, Acute Physiology and Chronic Health Evaluation (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, blood tests performed on the day of colistin initiation (creatinine, urea, albumin, C-reactive protein (CRP), hemoglobin, platelets, white blood cells, and lymphocyte count), use of vasoactive or inotropic (noradrenaline) agents on the day of colistin initiation, antibiotics used before or together with colistin such as meropenem and vancomycin, use of furosemide, number of days for AKI development, renal replacement therapy (RRT), and mortality status were recorded by analyzing hospital automation systems and patient files.The KDIGO criterion was used to define AKI: Stage I: serum creatinine level 1.5 to 1.9 times or ≥0.3 mg/dL from baseline or the urine output <0.5 mL/kg for 6 to 12 hours; Stage II: serum creatinine level 2 to 2.9 times or the urine output 0.5 mL/kg for more than 12 hours; and Stage III: serum creatinine level 3-times the basal value or >4 mg/dL, RRT required, urine output <0.3 mL/kg for more than 24 hours, or anuria for more than 12 hours.Patients under 18 years of age, patients with COVID-19, patients with chronic renal failure, and those receiving colistin for <2 days were excluded from the study.The study was approved by the Bolu Abant Izzet Baysal University Clinical Research Ethics Committee (decision no.2023/50, dated March 14, 2023).

Statistical analysis
Statistical analyses were performed using SPSS statistical software for Windows (version 20; IBM, Armonk, NY).The Kolmogorov-Smirnov test and distribution histograms were used to assess the normality of the assumption of distributions.The Mann-Whitney U test was used to compare non-normally distributed variables, and descriptive statistics are shown as median (1st-3rd quartile value).Pearson chi-squared test was used to compare categorical data.Spearman correlation test was used for the correlation analysis.The predictive values of these parameters were evaluated using multivariate regression analysis.Receiver operating characteristic (ROC) analysis was used to evaluate the classification ability of the parameters.Area under the curve (AUC) ± standard error, cutoff value, and sensitivity and specificity of the parameters were expressed using ROC analysis.P < .05 was considered statistically significant.
When we analyzed the 2 groups as survival and deceased, no significant difference was found between the 2 groups in terms of sex and comorbidities.AKI (P < .001),noradrenaline use on the day of colistin initiation (P < .001),meropenem use on the day of colistin initiation (P = .011),age (P < .001),APACHE II score (P < .001),SOFA score (P < .001),serum CRP level (P < .001)and serum urea level (P = .004)were significantly higher in the deceased group than the survival group.Further, serum lymphocyte count (P = .03)and serum albumin level (P < .001)were significantly lower in the deceased group.Patients who developed AKI and required RRT (P < .001)and patients who developed AKI after colistin use (P = .039)were significantly higher in the deceased group (Table 3).
A multivariate logistic regression analysis revealed that noradrenaline infusion on the day of colistin initiation (P = .003),high serum creatinine level (P = .003),and furosemide use (P = .032)were the risk factors for the development of AKI in patients administered colistin (Table 4).Further ROC analysis of these parameters revealed that a serum creatinine cutoff value of >1.1 was associated with a sensitivity of 70.49%, specificity of 83.33%, and AUC of 0.809 (95% CI); serum albumin cutoff value of <25 was associated with a sensitivity of 59.52%, specificity of 91.8%, and AUC of 0.807 (95% CI); serum CRP cutoff value of >91 was associated with a sensitivity of 90.16%, specificity of 61.9%, and AUC of 0.746 (95% CI); and serum urea cutoff value of >45 was associated with a sensitivity of 86.89%, specificity of 66.67%, and AUC of 0.781 (95% CI) (Table 5).

Discussion
Colistin, which was from use due to its serious adverse effects, has begun to be reused owing to the increasing carbapenem resistance of microorganisms and MDR.During prolonged hospitalizations in ICUs, gram-negative microorganisms, such as A baumannii, cause conditions such as pneumonia, sepsis, and septic shock, which may result in mortality.AKI can be influenced by drugs, conditions related to the patient in the ICU, and comorbidities.Shields et al [9] investigated the development and incidence of AKI in patients treated with colistin and found that 12% and 29% of patients developed AKI on day 2 and 7, respectively.Further, they observed that chronic liver disease, vancomycin use with colistin, and high-dose colistin were risk factors, and the KDIGO criterion was useful for the early diagnosis of AKI.Arrayasillapatorn et al [1] retrospectively analyzed the data of 412 patients and found that AKI developed in 68.5% of patients and that advanced age, the presence of previous AKI or elevated creatinine levels, and the use of vasopressors, diuretics, and vancomycin when colistin was initiated were the risk factors.
In their study, colistin-induced AKI was associated with mortality. [1]Ozel et al [10] applied colistin loading and maintenance therapy in their observational study and investigated colistinassociated renal damage using the RIFLE criterion.They found that preexisting high creatinine levels, advanced age, and high plasma colistin levels were risk factors for nephrotoxicity.
Khalifeh et al [11] diagnosed colistin-related AKI in 46.9% of 113 patients using the KDIGO criterion and found that low serum albumin levels and the simultaneous use of 2 or more nephrotoxic agents with colistin were risk factors for AKI.Al-Abdulkarim et al [12] defined renal damage according to the RIFLE criterion in patients receiving colistin for more than 72 hours.Colistin-related nephrotoxicity developed in 45.7% of the 70 patients.They identified advanced age and high-dose colistin use as the risk factors.In a laboratory study, intraperitoneal colistin was administered to mice, and increased levels of blood urea nitrogen, renal damage markers, and cell apoptosis were observed.In the same mouse group, the 200 µg/mL colistin dose significantly increased cell apoptosis. [13]Rabi et al [14] investigated the risk factors and the time of AKI development and found that patients who were initiated with colistin due to A baumannii, patients who used furosemide before and concomitantly, older patients, overweight patients, and patients with hypoalbuminemia were at higher risk for AKI development.In the same study, the mortality rate was higher in patients who developed colistin-induced AKI.
Kucuk et al [15] analyzed the relationship between dexmedetomidine and AKI in patients receiving colistin and found that 47% of the patients developed AKI after a mean of 5 days.In this study, advanced age, low glomerular filtration rate, and vasopressor use were associated with AKI development, whereas dexmedetomidine use was independently associated with lower AKI development.Notably, colistin was found to be unrelated to both AKI development and mortality when AKI was analyzed using the AKIN in patients receiving colistin and combination antibiotic therapy for MDR ventilator-associated pneumonia. [16]eng et al [17] examined adverse effects and mortality in patients receiving colistin in a multicenter study of 122 patients.They found that high SOFA scores, prolonged hospitalization, and the need for extracorporeal membrane oxygenation were independent risk factors for mortality, with a mortality rate of 29.5%.In the same study, AKI developed in 5 patients with previously high creatinine levels, according to KDIGO.In a multicenter study, Korkmaz Erken et al [18] investigated AKI using the RIFLE criterion in patients receiving colistin and found that 62.3% of patients developed AKI, with 66.9% mortality.In their study, the risk factors for AKI were high-dose colistin use, advanced age, previous AKI, hypertension, and male sex.
Rivero et al [19] evaluated renal damage in COVID-19 patients analyzing renal biopsy results and observed tubular epithelial loss due to nephrotoxic agents such as colistin using electron microscopy.Mazzitelli et al [20] compared cefiderocol-based versus colistinbased treatment regimens in their study, referring to the increase in carbapenem resistance during the COVID-19 pandemic, and  found that AKI development was higher in patients using colistin between the 2 groups; however, no difference was observed in mortality.In a review, Topete et al [21] stated that COVID-19 resulted in the increase the number of critically ill patients and evaluated the adverse effects and drug resistance inpatients using colistin.They concluded that critical patients with COVID-19   could be added to conditions such as hypoalbuminemia, septic shock, age, etc, which are effective in colistin nephrotoxicity.
In our study, analyzed the data of 103 patients treated with colistin for gram-negative MDR microorganisms.The AKIN, RIFLE, and the current version of the KDIGO criteria have been used in several studies.In our study, we used KDIGO as the AKI criterion.According to the KDIGO, AKI developed in 59.2% of patients, and RRT was required in 50.8% of these patients.The fact that almost 1 of every 2 patients did not require RRT suggests that these patients had stage-I-II AKI.In our study, the mortality rate was high (64.1%) in patients who developed colistin-induced AKI.Compared with the patients who did not develop AKI, we found that patients who developed AKI were older, had higher APACHE II and SOFA scores, had previously impaired renal function, had low serum albumin levels, and received nephrotoxic agents such as vasoactive agents, diuretics, and meropenem on the day of colistin initiation.A multivariate logistic regression analysis revealed that noradrenaline infusion, furosemide, and high serum creatinine levels on the day of colistin initiation were independent risk factors for AKI development in patients receiving colistin.Vasoactive agents increase blood pressure and impair tissue perfusion through vasoconstriction, which may increase the damaging capacity of colistin, an agent that promotes apoptosis.We believe that patients with renal damage due to other causes and impaired serum renal function may be more sensitive to colistin nephrotoxicity.Further, furosemide may increase the sensitivity to colistin because it may dysregulate the intravascular volume and cause electrolyte disturbance and AKI in critically ill patients.In our study, sex and comorbidities were not associated with AKI development.

Conclusion
Colistin is an antibiotic that has recently been increasingly used in the treatment of MDR gram-negative bacteria; however, it has serious adverse effects such as AKI.In this study, we analyzed the effective conditions for the development of AKI in patients receiving colistin.We found that patients with older age and hypoalbuminemia were at risk for AKI.Using multivariate regression analysis, we found that the use of vasoactive agents, elevated creatinine levels, and furosemide use were independent risk factors for AKI development.Notably, more randomized controlled studies are needed to define the risk factors for AKI.

Limitations
Our study has some limitations.First, it was a retrospective study.Second, we could not evaluate the intravascular volume status associated with renal injury.Third, although we determined the number of vasoactive agents used, we could not specify the infusion dose per kilogram.Further, we could not specify the colistin plasma level or colistin dose per kilogram.In addition, we could not record the potential nephrotoxic agents used by patients with comorbidities for a long time before ICU admission.Fourth, we did not specify the AKI stages according to the KDIGO criterion.

Table 1
Demographics of study population.

Table 2
Comorbidity, blood tests, and drug usage of patients with and without AKI.

Table 3
Comorbidity, blood tests, APACHE II, SOFAs, AKI status, and drug usage of patients deceased and survived groups.Acute Physiology and Chronic Health Evaluation, COPD = chronic obstructive pulmonary disease, CRP = C-reactive protein, DM = diabetes mellitus, HT = hypertension, RRT = renal replacement therapy, SOFAs = Sequential Organ Failure Assessment score, WBC = white blood cell.

Table 4
Multivariate logistic regression analysis of parameters.

Table 5
ROC analysis of parameters.
APACHE = Acute Physiology and Chronic Health Evaluation, AUC = area under the curve, CI = confidence interval, CRP = C-reactive protein, Hgb = hemoglobin, SOFAs = Sequential Organ Failure Assessment score, WBC = white blood cell.